Gary Ruvkun has made a career out of imagining the unimaginable, and of surrounding himself with like-minded thinkers who let the wheels of thought spin until they catch on something hard, gain traction, and take off.

In the early 1990s, the thoughts of Ruvkun and colleague Victor Ambros caught on the idea of microRNA, tiny strips of genetic material that behave differently from how scientists believed RNA could. That development eventually transformed our understanding of how our body’s cells go about their business, of how they turn DNA on and off to create the proteins that do much of the body’s work.

Until that time, scientists thought that proteins alone turned genes on and off, sped them up or slowed them down. Until then, RNA, a molecule related to DNA, was thought to carry out DNA’s genetic instructions, not mess them up.

Since then, science has come to understand that RNA, as well as proteins, can regulate DNA’s action. A new generation of scientists has turned to the study of microRNA, discovering that a wide array — as many as 1,000 different kinds in humans alone — exist in living things from plants to worms to flies to people.

The discovery netted Ruvkun, who is a professor in genetics at Harvard Medical School (HMS) and an investigator at Massachusetts General Hospital’s (MGH) Department of Molecular Biology and Center for Computational and Integrative Biology, this year’s Warren Triennial Prize, MGH’s highest award for research, and the Albert Lasker Basic Medical Research Award. He won both awards together with longtime collaborator Ambros, of the University of Massachusetts, and the Lasker with David Baulcombe, a British researcher who found similar molecules in plants. The Lasker Foundation described microRNA as “pivotal regulators” of both normal and disease physiology and praised the “open-mindedness, wisdom, and experimental finesse” that allowed the three researchers to see something wholly new in the landscape of molecular genetics.

Open-mindedness is nothing new to Ruvkun. Colleagues and former fellows describe a man in love with ideas — even bad ones. Brainstorming sessions are a regular feature of daily lab tea breaks, and no idea is too strange to be welcome.

Ruvkun believes that a blizzard of thought helps good ideas drift down. In addition to continuing to work on microRNA, Ruvkun’s lab is also working on how longevity is genetically regulated and is beginning a project, with Massachusetts Institute of Technology (MIT) planetary scientist Maria Zuber, to detect life on Mars.

“He likes wacky ideas. The point of an idea is not to be right but to stimulate thinking and experimentation,” said Garth Patterson, a postdoctoral fellow in Ruvkun’s lab from 1994 to 1998 and now an assistant dean at Rutgers University. “It was a blast, … with the intellectual ferment of the postdocs and all those great graduate students.”

The freedom of thought in Ruvkun’s lab doesn’t mean scientific sloppiness, however. Ruvkun has a knack for picking the most pertinent ideas from the intellectual storm he instigates. He also has a reputation for creative but exacting science. Fellows and graduate students understand that their creative freedom is supported by a solid investigational foundation.

“The topics Gary chose to work on were fundamentally important. We all thought we were making fundamental breakthroughs with Gary. We actually felt like we were contributing,” said Frank Slack, a postdoctoral fellow in Ruvkun’s lab from 1994 to 1999 and today an associate professor of molecular, cellular, and developmental biology at Yale University.

Imagining space

Freedom of thought and a passion for science have marked Ruvkun from the start. During a boyhood in the 1950s, he was fascinated by televised space launches, mesmerized even during countdown holds, when crew-cut scientists in canned interviews explained orbits and apogees and the perils of space.

“It was way better than school,” Ruvkun recalls, “all this totally cool stuff, not ‘How many pecks of apples in a bushel?’ For five years of my life, I got my education from TV.”

As a teenage ham radio buff, Ruvkun learned about circuits, something he says still influences how he views biology and thinks about systems. Ham radio also exposed him, for the first time, to the power of collegiality at ham radio meets, where like-minded people, from factory workers to scientists, shared their passion.

“When I went to my first scientific meeting, I was like, ‘OK, this is just a hamfest,’” Ruvkun said.

After high school, Ruvkun attended to the University of California, Berkeley. He arrived in the fall of 1969, stepping onto campus during a time of freethinking and foment. He was swept up in the passion of the times, marching and protesting. He learned the street lessons of the day — that applying raw eggs to your eyes, nose, and mouth would protect from tear gas, that society’s establishment wasn’t as benevolent as he had been taught, and that the scientific enterprise is deeply embedded in politics, as evidenced by the research that led to nuclear weapons, which reverberated in the politics of the Cold War and the Vietnam War — and that continues to influence politics today.

While many of Ruvkun’s peers protested their college years away, Ruvkun himself was too interested in his studies for that to happen. He marched, but also went to classes.

“There was a lost generation of my cohort that didn’t get an education in anything but rhetorical flourish,” Ruvkun said. “I had the nerdiness to keep my day job and learn the things that interested me.”
Ruvkun did well in his classes. He found himself drawn to study physics, enticed by the knottiness of its problems, despite the negative view of physicists held by his peers.

“The non-obviousness of quantum mechanics was hypnotically interesting,” Ruvkun said. “I had a sense that this might be too hard for me … that I’m barely hanging on, but I found it beyond interesting, so I kept at it.”

Ruvkun found it nearly impossible not to be affected by the times at Berkeley, however. He began to consider whether there was a way to put his passion for science to a good social use. Medical school seemed an appropriate postgraduation option, but he would have to augment his physics classes with biology. He wound up taking molecular biology and soon discovered that he was hooked on genetics.

“I learned bacterial genetics and just thought it was the coolest thing,” Ruvkun said.

Ruvkun graduated in 1973 with a degree in biophysics and applied to medical school. Today he views the rejections that poured in — he didn’t get accepted anywhere — as a confirmation of the interviewers’ wisdom. He is certain they picked up on the fact that his heart wasn’t really in medicine, that he felt “pushed from behind” by the politics of the era, rather than moving toward something he was excited about.

With no other prospects in sight, Ruvkun went exploring. He drove north through California into Oregon, living out of a 1969 Dodge van his parents bought him. Over a beer in a bar in Eugene, he heard about a tree-planting co-op, whose members lived and worked communally in the mountains.

Intrigued, he joined what he described as a “whole rogue’s gallery of hippie types.” He planted trees for six months, getting to know other co-op members, as well as the loggers and other working stiffs they met in the bars at the end of the day.

“They were all seekers, thinkers, and radicals. It was a tribe, it had a kind of utopian vision of a worker co-op,” Ruvkun said. “It was hard work, but a huge amount of fun.”

After leaving the co-op, Ruvkun followed up his northern adventure by heading south. With no other goal than to reach Tierra del Fuego, the archipelago at the continent’s southern tip, he and a friend set off on what Ruvkun described as a “huge adventure.” The pair traveled by bus and train, crashing at dollar-a-night hotels and not worrying about amenities or reservations.

Eventually, however, the novelty wore off and one dilapidated bus ride looked and felt like another. After six months, he began to think about what to do when he got back. It was during this time that he stopped at the Bolivian-American Friendship Club, picked up an issue of Scientific American and spent the day just sitting and reading.

The grip in which the magazine held him made him realize that science was not just a passing fancy for him. It was a deep fascination and, if he was smart, he would make it part of his future.

When he got home, he applied to graduate school, getting accepted into Harvard’s biophysics program, which Ruvkun described as freewheeling, with few constraints.

He arrived in 1976, just two years after the publication of the first major paper describing recombinant DNA — where part of the DNA of one creature is inserted into that of another. Ruvkun said there was a growing sense that a scientific revolution was brewing.

“When I got to Harvard and saw recombinant DNA, I knew it was a revolution. I wanted to jump on top of it,” Ruvkun said. “I think the important thing about physicists coming into biology is that they have seen revolutions, cataclysmic change, with relativity and quantum mechanics. Anyone coming from physics knows how to recognize those things.”

He settled in the lab of Fred Ausubel, today a genetics professor at HMS and MGH who then was a young assistant professor nurturing a year-old lab. It was in Ausubel’s lab that Ruvkun learned all about DNA and how to manipulate it.

“Fred’s lab was kind of an island of thinking genetically. What I really learned in five years there was a huge amount of fluency in DNA work,” Ruvkun said.

It was apparent to Ausubel that Ruvkun had a good scientific mind. He was the best of a good group of graduate students and built up an impressive publication record, publishing five papers as the first author, three in major journals. Perhaps most importantly, Ausubel said, was that Ruvkun had an instinctive sense of the most important questions to pursue.

“It’s really whether you have a nose for doing science, whether you have a sense of how your work fits into the big picture, whether you know what experiments to do, what questions to ask to advance the entire field. That’s a key quality that distinguishes people [who are successful in science],” Ausubel said.

Worming into deep insights

After Ruvkun received his doctorate in 1982, Ausubel nominated him for a Harvard junior fellowship. During his fellowship years, he did research with Walter Gilbert (who won the Nobel Prize in Chemistry in 1980 for his work determining the base sequences of DNA and RNA) at Harvard and with Robert Horvitz (who would win the Nobel Prize in Physiology or Medicine in 2002 for his work determining the genetic roots of cell death) at MIT.
Horvitz introduced Ruvkun to the worm C. elegans, which Horvitz used as a model organism in his studies. C. elegans is a roundworm about a millimeter long that in nature eats bacteria in decaying plant matter. In the lab, the worm has become an important model organism because it has both the same organs found in more complex animals, yet itself is exceedingly simple. It is so simple, in fact, that an adult female worm has just 959 cells in its entire body, an amount low enough that scientists have been able to trace each cell’s lineage back to the dividing egg.

The worm’s simplicity allows scientists to understand its development and gain insights into more complex organisms. Once in Horvitz’s lab, Ruvkun met Ambros, who at the time was a postdoctoral fellow studying the worm’s passage through developmental phases from egg to adult.

Ambros was specifically working on a gene called lin-4, without which the worm got stuck in juvenile phases. He was also exploring a second gene, lin-14, that seemed to have the opposite effect. Without lin-14, worms would seemingly skip early phases and develop characteristics of more mature worms.

Ruvkun’s arrival began a friendship and a scientific relationship with Ambros that has endured to today. The two knew that the lin-4 and lin-14 genes were linked and that they together controlled the pace at which the worms developed, but they didn’t know how. Ruvkun, Ambros said, brought to the lab his expertise in working with DNA. Together, he and Ambros cloned lin-14 at a time when cloning was still novel and difficult.

“He brought to bear his molecular ingenuity,” Ambros said. “Each gene required a case-by-case method. Gary really did that. He invented ways for carrying out these clonings. He was constantly teaching people methodology new to them.”

By the mid-1980s, both Ruvkun and Ambros had moved on, establishing labs independently. Ruvkun was at MGH, while Ambros was first an assistant professor and then associate professor at Harvard’s Department of Cellular and Developmental Biology.

Though they had separate labs, they continued to work on the problem, communicating and even sharing data. Ruvkun’s lab figured out that one of the genes, lin-14, was the master gene, producing proteins that spurred early development and then were shut off, allowing later development to proceed. Ambros, for his part, figured out that it was the product created by the other gene, lin-4, that stopped lin-14 when early development was complete.
    But both men puzzled over how it did that. 

Ambros’ lab tried to isolate whatever it was that stopped lin-14 from producing protein. They expected it to be another protein, since it was thought at the time that proteins were what regulated genes.

In June 1992, Ruvkun said Ambros called him and said he didn’t think it was a protein, but it might be a tiny piece of RNA. If it was, the two realized, it could block lin-14 from working by binding to the messenger RNA that carried instructions to the cell’s protein-making machinery.

Molecules of both DNA and RNA work in similar ways, by stringing together a handful of smaller molecules, called bases, each of which attach only to complementary bases. That molecular pickiness is what creates DNA’s famous double helix structure and is what makes up the genetic code. That specificity also allows RNA molecules to copy DNA’s cellular blueprints — in the form of what might be described as an “opposite copy” — and carry them to the cell’s protein-making machinery.

If it was an RNA that blocked the lin-14 gene, it would be apparent because it would have the complementary sequence of bases.

Given that Ambros had the sequence of the blocking molecule and Ruvkun had the sequence of lin-14, the two labs exchanged data. All the two had to do to confirm it was indeed a new kind of RNA would be to see if the bases matched.

Ambros said later that he almost put off looking at the data, thinking that after 10 years of work, it really just couldn’t be that simple.

“I remember thinking to myself that I’d better look at it,” Ambrose said. “Because it can’t be as simple as an antisense RNA, but if it is….”

At the same time, Ruvkun was looking at the same data, thinking the same thing.

“We called each other up, ‘Do you see it?’ We read off the sequence,” Ambros said. “We thought, this is great, we’re seeing it together.”

“The response of both of us was, ‘This is just too pretty to be wrong,’” Ruvkun said.

When the word got out, many thought it was an oddity limited to the worm Ruvkun and Ambros were working on. It didn’t help that neither of the genes were found in other creatures. Then, in 1999, graduate student Brenda Reinhart along with postdoctoral fellow Frank Slack found a second gene for microRNA, called let-7. When postdoctoral fellow Amy Pasquinelli, along with Reinhart, found that this microRNA is also present in humans, fruit flies, and a Noah’s Ark of other animals, microRNAs finally showed up on the radar screen of the rest of biology. It turned out to be rather simple, after let-7 was identified, to find its counterparts in other organisms.
In the intervening years, the rapid advance of technology had made life easier for molecular geneticists. Once they found let-7’s sequence, they were able to use their computers to do a database search, looking for similar 20-base sequences in other creatures. They used their dial-up modem to connect to a database and 30 seconds later had hits in the genomes of flies and humans.

From there, scientists realized that a new way of regulating gene expression had been found and the race was on. Today, scientists know that microRNA bind to the messenger RNA that carry the genetic instructions from the DNA to the cell’s protein-making factory, called a ribosome. With the microRNA attached, the messenger RNA can’t do its job, so expression of that gene is stopped. Scientists believe the human genome contains 500 to 1,000 genes for microRNA. These microRNA control as many as a third of all human protein-coding genes, including those involved in embryonic development, muscle function, heart disease, and cancer.

Ruvkun and Ambros remain thankful for their long collaboration. Though perhaps unusual in some scientific disciplines, Ruvkun and Ambros say their teamwork is a reflection not only of their friendship, but also of the great sense of community that exists among biologists working on C. elegans.

“We hang out as much as we can … but there was a little spark of competition,” Ambros said. “We knew each would benefit from the other’s data, but we also knew we couldn’t leapfrog the other on our own.”